Project 1 has the overall theme of studying the immuno-genetic epidemiology of complex malaria in India as part of the Center for the Study of Complex Malaria in India. Single-species infections by a malaria parasite, 'successive' (one after another) infections, mixed-species (two or more concurrent) infections, and mixed genotype infections will be detected during a 5 year longitudinal study at three eco-epidemiologically different field stations in India, and used in four sub-Projects. Sub-Project 1 will investigate the development of natural immunity to malaria in individuals: its association with prior exposure to malaria, parasite species, and parasite genetic diversity. Sub-Project 1 will also study complex mixed-species infections, and the differing ratios of Plasmodium species in infections across geography and time. Sub-Project 2 will determine the genetic diversity of the highly variable var gene family in Indian malaria parasites, which is thought to help the parasite evade the human immune system, and assess how var diversity relates to development of natural resistance to malaria by hosts. Sub-Project 3 will analyze the inflammatory immune response to malaria in Indian subjects, particularly in relation to production by the parasite of uric acid (a recently proposed mediator of malaria-induced inflammation), and the severity of malaria as a function of diversity of dendridic cells which control the activation of human immune response. Sub-Project 4 will investigate whether naturally-immune individuals in India harbor specific antibodies to regions of a known malaria antigen, CSP. Research Project 1 overall thus advances the CSCMi goals of developing the data and evidence-based strategies needed to support the intervention and control programs of Indian government organizations, and building research capacity in India and help train the next generation of malaria and mosquito vector biologists.